Skin care composition

ABSTRACT

There are provided compositions which include a retinoid and preferably retinal; a dermatologically active acid; and a volatile base, such as ammonium hydroxide. Another embodiment of the invention includes compositions comprising a retinoid and preferably retinal; a dermatologically active acid; a volatile base; and a second neutralizing agent. There are also provided compositions which include a retinoid, a neutralized ammonium salt of a dermatologically active acid, and optionally a neutralized salt, other than ammonium salt, of an acid. Further provided are methods for reducing fine lines, wrinkles, skin roughness, and pore size and for increasing the clarity of a skin surface, cellular turnover, skin radiance, skin smoothness, skin permeation or collagen synthesis in a mammal in need thereof. Compositions as described above are administered topically to the skin of the animal.

This application is a continuation-in-part of U.S. Ser. No. 09/436,867,filed Nov. 9, 1999, now U.S. Pat. No. 6,544,531, which is acontinuation-in-part of U.S. Ser. No. 09/325,452, filed Jun. 3, 1999,now U.S. Pat. No. 6,521,237, which claims priority from U.S. Ser. No.60/107,956, filed Nov. 12, 1998, all of which are herein incorporated byreference.

FIELD OF THE INVENTION

This invention relates to skin care compositions which include, in asingle formulation, the beneficial ingredients for aging or photodamagedskin, retinol and an acid.

BACKGROUND OF THE INVENTION

Retinol or vitamin A alcohol is useful in the reduction of fine lines,wrinkles, and mottled hyperpigmentation in skin. Hydroxy acids, andparticularly alpha-hydroxy acids, are useful in increasing the clarityof the skin surface, increasing cellular turnover, and increasing skinradiance and smoothness. Ascorbic acid has skin permeation and collagensynthesis activity.

Retinol is physically unstable and rapidly degrades when stored at a pHbelow about 5. Acids such as hydroxy acids, and particularlyalpha-hydroxy acids and ascorbic acid, on the other hand, are not activein increasing skin cell turnover, exfoliation, skin permeation, and/orcollagen synthesis at pHs above about 5.

Consequently, retinol and hydroxy acids and/or ascorbic acid havegenerally been packaged separately. Retinol typically is packaged in avehicle at a pH above about 5, while alpha-hydroxy acids and ascorbicacid are packaged at a pH of about 4 or below. Therefore, one must applytwo separate products in order to achieve the benefit of both of theseingredients.

The present inventors have discovered a single composition which includeboth of these ingredients, in which both of these ingredients arestable, and in which both of these ingredients are active uponapplication to the skin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic illustration of skin pH over time after treatment.

FIG. 2 is a graphic illustration of cell proliferation measured as slopeof fluorescence after treatment.

FIG. 3 is a graphic illustration comparing the activity of ammoniumhydroxide and sodium hydroxide neutralized alpha-hydroxy acids incombination with retinol.

FIG. 4 is a graphic illustration of skin pH over time before and aftertreatment.

SUMMARY OF THE INVENTION

According to one embodiment of the present invention there are providedcompositions which include:

(A) a retinoid and preferably retinol;

(B) a dermatologically active acid; and

(C) a volatile base, such as, for example, a volatile compoundcomprising an amine such as ammonium hydroxide or 2-dimethylaminoethanol(N,N-dimethylethanolkamine or DMAE). Volatile bases have a vaporpressure typically below atmospheric pressure, preferably below about700 mm Hg, and more preferably below about 600 mm Hg. The volatile basepreferably evaporates upon contact with skin. The compositionspreferably contain an acid neutralizing effective amount of ammoniumhydroxide or DMAE.

Another embodiment of the present invention provides compositions whichinclude:

(A) a retinoid and preferably retinol;

(B) a dermatologically active acid;

(C) a volatile base; and

(D) at least one second neutralizing agent.

According to yet another embodiment of the present invention, there areprovided compositions which include:

(A) retinol; and

(B) a neutralized ammonium salt of a dermatologically active acid (e.g.the ammonium salt formed by a volatile compound comprising an amine suchas ammonium hydroxide or a volatile alkanolamine such as DMEA). Examplesof such salts include ammonium glycolate and N₁N-dimethylethanolammoniumglycolate. Optionally, a second neutralized salt of a dermatologicallyactive acid is included in the compositions.

Further provided are methods for reducing fine lines, wrinkles, skinroughness, and pore size and for increasing the clarity of a skinsurface, cellular turnover, skin radiance and skin smoothness in ananimal, for example, a mammal, such as a human, in need thereof.Compositions as described above are administered topically to the skinof the animal.

Methods for preparing the compositions above are also provided.

Other features and advantages of the invention will be apparent from thedetailed description of the invention, the drawings, and the claims.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present formulations provide compositions whichhave a storage pH of about 5 or higher. This provides storage stabilityfor the retinoid compound (e.g. retinol). However, the pH of thesecompositions drops to below 5 when applied to the skin. This allows thehydroxy acid(s) and/or other skin beneficial acids(s) therein to becomeactive upon application of the composition to the skin.

Retinoids suitable for use in the present invention preferably areunstable or pH sensitive in that they are chemically and physicallyunstable at relatively low pH such as, for example a pH below about 5,such as retinol and derivatives thereof. Suitable retinoids include, butare not limited to retinol and derivatives thereof, such as retinylpalmitate and retinyl acetate; retinaldehyde; and like compounds thatbind to retinoid receptors.

Retinal is also known as vitamin A alcohol. Retinol is chemically andphysically unstable at a pH below about 5. It is useful in reducing finelines at wrinkles in skin. It is also useful in reducing mottledhyperpigmentation of skin. Other retinoids having pH dependent stabilitymay also be used in combination with or in place of retinol in thepresent invention.

The dermatologically active acid may be a cosmetically active acid or apharmaceutically active acid, such as, for example, a hydroxy acid,ascorbic acid or a derivative thereof, lipoic acid, dihydrolipoic acid,or a combination thereof.

Hydroxy acids useful in the present invention are either alpha- orbeta-hydroxy acids, poly-hydroxy acids, or any combinations of any ofthe foregoing. Preferably, the hydroxy acid is an alpha-hydroxy acid.Examples of alpha hydroxy acids include, but are not limited to lacticacid, glycolic acid, malic acid, tartaric acid, pyuric acid, citricacid, or any combination of any of the foregoing. Special mention ismade of glycolic acid.

Beta-hydroxy acids include, but are not limited to, salicylic acid.

Other suitable hydroxy acids are disclosed in U.S. Pat. No. 5,889,054,which is hereby incorporated by reference.

Other acids suitable for use in the present invention include, but arenot limited to, ascorbic acid and derivatives thereof, lipoic acid, anddihydrolipoic acid. Suitable ascorbic acid derivatives include, but arenot limited to, magnesium ascorbyl phosphate; sodium ascorbyl phosphate;sodium ascorbate; and ascorbyl glucosides.

Suitable second neutralizing agents which may be included in thecomposition include, but are not limited to, alkali hydroxides, such assodium hydroxide and potassium hydroxide; and organic bases, such asalkanolamines, including, but not limited to, diethanolamine,triethanolamine, DMAE and aminobutanol; ammonium hydroxide, and aminoacids, including, but not limited to, arginine and lysine; and anycombination of any of the foregoing. A preferred second neutralizingagent is sodium hydroxide.

When utilized, ammonium hydroxide is typically added as a solutioncontaining from about 27 to about 31 percent by weight of ammoniumhydroxide based upon 100 percent by weight of total ammonium hydroxidesolution.

The compositions of the present invention may also include otheradjuvants, such as, for example, vehicles including, but not limited to,water or alcohol; humectants, including, but not limited to, glycerin;buffering agents including, but not limited to, citric acid and sodiumcitrate; viscosity adjusters, including, but not limited to, carbomergelling agents, gum derivatives, and other viscosity controlling,decreasing, and increasing agents; preservatives including, but notlimited to, parabens, such as methylparaben and propylparaben, andphenoxyethanol; emulsifiers including, but not limited to, polysorbate80, glyceryl distearate, POE 10 stearyl ether, steareth 10, ceateareth20 and stearyl alcohol, and ceteareth 20 and cetearyl alcohol;conditioning agents including, but not limited to, octylhydroxystearate, stearyl alcohol, lactose, and dimethicone; emollientsincluding, but not limited to, cholesterol NF, petrolatum, mineral oilsand esters including, but not limited to, isopropyl myristate, isopropylpalmitate, 1-decene polymer (hydrogenated), and C₁₂-C₁₅ alcoholbenzoates; thickeners, including, but not limited to, binders,polyacrylamide, C₁₃-C₁₄ isoparafin, and laureth-7; antioxidants,including, but not limited to ascorbic acid, butylated hydroxytoluene(BHT), tocopheryl acetate, and the like; UV stabilizers; UV radiationabsorbers (sunscreen filters); fragrances; colorants; chelating agents,including, but not limited to, disodium ethylenediaminetetraacetate(EDTA); or any combinations of any of the foregoing. Examples of theseadjuvants are disclosed in the International Cosmetic IngredientDictionary and Handbook, 7^(th) Ed. (1997)

These compositions can be formulated as creams, gels, or liquids, andpreferably are prepared as lotions. These compositions can be preparedas liposomes, including, but not limited to, unilamellar, multilamellar,or paucilamellar vesicles; nanospheres; microsponges; emulsions, such asa multiple emulsion and a cleansing emulsion; or any combination of anyof the foregoing by methods known to those skilled in the art. In oneembodiment, the composition is prepared as a paucilamellar vesicle (e.g.containing the retinoid and/or the dermatologically active acid or saltthereof) having, for example, between 2 and 10 lipid bilayers and alipophilic core which may contain an apolar oil or wax.

The compositions are typically neutralized to a pH above about 4.5,preferably ranging from about 4.5 to about 8 and most preferably fromabout 5 to about 6. The amount of the volatile base (e.g. ammoniumhydroxide or DMAE) and optionally second neutralizing agent usefulherein is that amount sufficient to adjust the pH of the compositions tothe above pH ranges. The amount of volatile base in the compositions ofthe present invention is preferably that amount sufficient to adjust thepH of the acid from about 4.0 or less to at least about 5.

A preferred method of preparation includes neutralizing the compositionto a pH of about 4.0 or less with the aforementioned second neutralizingagent and then further neutralizing the composition to a pH of at leastabout 5 with the volatile base.

The amount of retinoid in these compositions is typically a fine line-,wrinkle-, or mottled pigmentation-reducing effective amount. The amountof retinoid (e.g., retinol) is at least about 0.001 percent by weight,(e.g., about 0.01 to about 10 percent, such as about 0.01 to about 1percent), based upon 100 percent by weight of total composition.

The amount of acid, ammonium salt of acid, or other salt of the acid istypically a skin surface clarity, cellular turnover-, skin radiance-,skin smoothness-, skin permeation-, or collagen synthesis-increasingeffective amount. Preferably, this amount ranges from about 0.1 to about20 percent by weight based upon 100 percent by weight of totalcomposition. More preferably this amount ranges from about 1 to about 12percent by weight, and most preferably, this amount is from about 4 toabout 8 percent by weight, based upon 100 percent by weight of totalcomposition.

The composition preferably contains from about 1 to about 99 percent,and more preferably from about 60 to about 95 percent by weight ofwater, based upon 100 percent by weight of total composition.

Generally, the composition contains sufficient thickener to impart bodyto the composition without causing it to become so viscous as to hinderspreadability of the composition. The composition also preferablycontains up to about 5 percent by weight of a viscosity adjuster, up toabout 20 percent by weight of an emollient, from about 0.1 to about 10percent by weight of an emulsifier, up to about 5 percent by weight of aspreading agent, up to about 10 percent by weight of a thickener, apreservative, a chelating agent, and a humectant, based upon 100 percentweight of total composition. More preferably, the composition containsfrom about 0.1 to about 2 percent by weight of a viscosity adjuster,from about 3 to about 5 percent by weight of an emulsifier, from about 1to about 2 percent by weight of a spreading agent, an antimicrobiallyeffective amount of a preservative, and from about 3 to about 5 percentby weight of a thickener, based upon 100 percent weight of totalcomposition.

Without being bound by any theory, applicants believe that by using asalt of the acid and a volatile base, the storage pH of the presentcomposition can remain above 5, thereby providing a stable atmospherefor the retinol or any other pH sensitive ingredient. However, whenapplied to the skin, the pH of the salt of the acid changes byvolatilization of the volatile base (e.g., the ammonium). The pH thendrops to a range in which the acid can cause beneficial changes.

The compositions can be applied topically to a mammal, and preferably ahuman, in need of a retinoid, acids, or a combination thereof.Typically, the amount applied will be that amount effective toaccomplish the purpose of application.

The following examples illustrate the invention without limitation. Allamounts are given as weight percentages based upon 100 percent by weightof total composition unless noted otherwise.

EXAMPLE 1

A retinol/alpha-hydroxy acid composition having the formulation of Table1 and a pH of about 6 and containing paucilamellar vesicles was preparedby a shear mixing method. The apparatus used to prepare the liposomes bythe shear mixing method is described in U.S. Pat. No. 4,895,452, whichis hereby incorporated by reference. A mixture containing theappropriate amounts of the ingredients for the lipid phase was heated ina container at about 75° C. until all of the lipids melted. The lipidmelt was then cooled to about 65° C. The ingredients for the aqueousphase were mixed together, heated to about 75° C. to dissolve them, andthen cooled to about 60° C. The lipid melt and aqueous phase mixturewere then poured into separate holding reservoirs of the shear mixingapparatus.

The positive displacement pump for the lipid melt and aqueous phasemixture feed lines were turned on. The feed rate was adjusted to 1 partlipid to 4 parts aqueous phase.

The aqueous phase mixture and lipid melt were fed through injection jetsinto a cylindrical mixing chamber tangentially with respect to thecylinder wall. In the mixing chamber, the two streams of flowing liquidintersect in such a manner as to cause shear mixing that leads to theformation of liposomes. The liposomes formed were then withdrawn throughan exit tube and transferred to a Cafero mixing vesicle. The liposomeswere cooled to 40° C., under mixing at 200 rpm. After cooling, thesingle addition components listed in Table 1, were added sequentially.The resultant mixture was then mixed at 200 rpm for about 30 minutes.The formulation was allowed to cool to room temperature under ambientconditions.

TABLE 1 Retinol/Alpha-Hydroxy Acid Liposome Formulation-pH6 % TRADE NAMECHEMICAL NAME FUNCTION WT/WT AQUEOUS PHASE Deionized Water D. I. WaterVehicle 60.93 Glycerin 916 Glycerin Humectant 4 Citric Acid Citric AcidBuffering 0.13 Agent Sodium Citrate Sodium Citrate Buffering 0.5 AgentSodium Chloride Sodium Chloride Viscosity 0.1 Adjuster Methyl ParaseptMethylparaben Preservative 0.25 Propyl Parasept PropylparabenPreservative 0.15 Tween 80 Polysorbate 80 Emulsifier 0.7 Glypure (70%)Glycolic Acid Skin 5.71 Conditioner NH4OH{circumflex over ( )} AmmoniumHydroxide (27 pH Adjuster 3.2 to 31% Solution) (pH = 6) LIPID PHASEWickenol 171 Octyl Hydroxystearate Conditioning 5.8 Agent Kessco GDSGlyceryl Distearate Emulsifier 2.8 Cholesterol, NH Cholesterol NFEmulsifer 1 BRIJ 76 POE 10 Stearyl Ether Emulsifer 1.4 Protocol ST 20GCeteareth 20 and Stearyl Emulsifier 3 Alcohol Protocol CS 20D Ceteareth20 and Stearyl Emulsifier 3 Alcohol Stearyl Alcohol Stearyl Alcohol Skin0.5 Conditioner Retinol 50CJ** V Retinol in Polysorbate- Skin 0.4 20Conditioner BHT BHT Antioxidant 0.1 Vitamin E Acetate Tocopheryl AcetateAntioxidant 0.1 SINGLE ADDITION COMPONENTS Emeressence 1160Phenoxyethanol Preservative 0.73 Dimethicone 47V 100 Centistoke Skin 2.5Dimethicone Conditioner Sepigel 305 Polyacrylamide, C13-24 Thickener 3Isoparrifin and Laureth- 7 **Retinol 50CJ is available from BASF ofMount Olive, NJ, and contains 50% by weight of retinol. {circumflex over( )}Amount of NH₄OH required to reach pH of 6 is estimated; each batchwill be titrated to pH = 6.

The formulation was applied to the skin, and the pH of the skin wasmeasured over time. Results are illustrated in FIG. 1. The pH of thepreparation dropped to about 4.1 within 15 minutes of application. Thisreduced the skin pH to about 4.

COMPARATIVE EXAMPLE 1A

A retinol/alpha-hydroxy acid containing composition having theformulation of Table 2 and a pH of about 4 was prepared as described inExample 1. The amount of ammonium hydroxide in this composition wasapproximately half the amount incorporated in the composition of Example1.

TABLE 2 Retinol/Alpha-Hydroxy Acid Liposome Formulation - pH 4 TRADENAME CHEMICAL NAME FUNCTION % WT/WT AQUEOUS PHASE (qs with DI water)Deionized Water D. I. Water Vehicle 62.43 Glycerin 916 GlycerinHumectant 4 Citric Acid Citric Acid Buffering 0.13 Agent Sodium CitrateSodium Citrate Buffering 0.5 Agent Sodium Chloride Sodium ChlorideViscosity 0.1 Adjuster Methyl Parasept Methylparaben Preservative 0.25Propyl Parasept Propylparaben Preservative 0.15 Tween 80 Polysorbate 80Emulsifier 0.7 Glypure (70%) Glycolic Acid Skin 5.71 ConditionerNH₄OH{circumflex over ( )} Ammonium Hydroxide pH Adjuster 1.7 27 to 31%Solution (pH = 4) LIPID PHASE Wickenol 171 Octyl Conditioning 5.8Hydroxystearate Agent Kessco GDS Glyceryl Distearate Emulsifier 2.8Cholesterol, NH Cholesterol NF Emollient 1 BRIJ 76 POE 10 Stearyl EtherEmulsifer 1.4 Protocol ST 20G Ceteareth 20 and Emulsifier 3 StearylAlcohol Protocol CS 20D Ceteareth 20 and Emulsifier 3 Stearyl AlcoholStearyl Alcohol Stearyl Alcohol Skin 0.5 Conditioner Retinol 50CJ**Retinol in Skin 0.4 Polysorbate-20 Conditioner BHT BHT Antioxidant 0.1Vitamin E Tocopheryl Acetate Antioxidant 0.1 Acetate SINGLE ADDITIONCOMPONENTS Emeressence 1160 Phenoxyethanol Preservative 0.73 Dimethicone47V 100 Centistoke Skin 2.5 Dimethicone Conditioner Sepigel 305Polyacrylamide, C₁₃₋₂₄ Thickener 3 Isoparrifin and Laureth-7 **Retinol50CJ is available from BASF of Mount Olive, NJ, and contains 50% byweight of retinol. {circumflex over ( )}Amount of NH₄OH required toreach pH of 4 is estimated.

The formulation was applied to skin, and the pH of the skin was measuredover time. Results are illustrated in FIG. 1.

COMPARATIVE EXAMPLE 1B

A retinol/alpha-hydroxy acid containing composition was prepared asdescribed in Example 1 above, except sodium hydroxide was substitutedfor the ammonium hydroxide.

The formulation was applied to skin, and the pH of the skin was measuredover time. Results are illustrated in FIG. 1.

COMPARATIVE EXAMPLE 1C

An alpha-hydroxy acid containing composition having 8 percent by weightsodium glycolate at a pH of about 3.5 and no retinol was prepared asdescribed in Example 1 above.

The formulation was applied to skin, and the pH of the skin was measuredover time. Results are illustrated in FIG. 1.

EXAMPLE 2

A composition containing 0.15 percent by weight of retinol and 4 percentby weight of glycolic acid, neutralized with ammonium hydroxide to a pHof about 6, was prepared as described in Example 1 above.

An in vivo study of proliferative activity on skin was conducted. Themarker of proliferative activity is an increase in fluorescent signal inthe ultraviolet portion of the light spectrum. Over the course of 11days of application, the fluorescence of the epidermis (exciting with296 nm radiation, monitoring fluorescence at 340 nm) increases withincreased proliferation activity. This fluorescence marker alsoincreases after another proliferation inducing treatment such astape-stripping, and has been shown to correlate with increased cellturnover-rate as measured by increased loss of epidermal stain, dansylchloride.

The slope of the increased fluorescence is illustrated in FIG. 2.

COMPARATIVE EXAMPLE 2A

An in vivo study as described in Example 2 was conducted using apreparation containing no glycolic acid or retinol at pH 6 (placebo).

The slope of the increased fluorescence is illustrated in FIG. 2.

COMPARATIVE EXAMPLE 2B

An in vivo study as described in Example 2 was conducted using apreparation containing 4 percent by weight of partially neutralizedglycolic acid at pH 4 without retinol (Avon ANEW®).

The slope of the increased fluorescence is illustrated in FIG. 2.

COMPARATIVE EXAMPLE 2C

An in vivo study as described in Example 2 was conducted using apreparation containing 8 percent by weight of glycolic acid partiallyneutralized at pH 3.8 without retinol (Neutrogena HEALTHY SKIN®).

The slope of the increased fluorescence is illustrated in FIG. 2.

COMPARATIVE EXAMPLE 2D

An in vivo study as described in Example 2 was conducted on untreatedskin.

The slope of the increased fluorescence is illustrated in FIG. 2.

FIG. 2 illustrates a significant increase in fluorescence activity and,therefore, cell proliferation in the retinol/glycolic acid preparationof Example 2 in comparison with both a placebo (Example 2A) anduntreated skin (Example 2D).

FIG. 2 also illustrates a significant increase in fluorescence activityand, therefore, cell proliferation in the retinol/glycolic acidpreparation of Example 2 which is similar to that of glycolic acidcontaining products having pH=s of about 4 (Comparative Examples 2B-D).

EXAMPLE 3

A composition containing 0.15 percent by weight of retinal and 4 percentby weight of glycolic acid neutralized to pH 5.5 with ammonium hydroxideas in Example 1 was prepared.

Fluorescence was measured as in Example 2. Results are illustrated inFIG. 3.

COMPARATIVE EXAMPLE 3A

A composition containing 0.15 percent by weight of retinol and 4 percentby weight of glycolic acid neutralized to pH 5.5 with sodium hydroxideas in Example 1 was prepared.

Fluorescence was measured as in Example 2. Results are illustrated inFIG. 3.

COMPARATIVE EXAMPLE 3B

The fluorescence of untreated skin was measured as in Example 2. Resultsare illustrated in FIG. 3.

FIG. 3 illustrates that while ammonium glycolate (Example 3) dissociateswhen applied to the skin, sodium glycolate apparently does not(Comparative Example 3A). The latter results in little change inproliferative activity of the skin, and thus no apparent skin benefit.

EXAMPLE 4

A composition prepared as in Example 1 was stored for 13 weeks at 40° C.(simulating 2 years of ambient aging). This preparation retained 87% ofthe original retinol content after storage.

COMPARATIVE EXAMPLE 4A

A composition prepared in Comparative Example 1A was stored for 13 weeksat 40° C. (simulating 2 years of ambient aging). This preparationretained only 52% of the original retinol content after storage.

EXAMPLE 5

A retinol/alpha-hydroxy acid containing composition having theformulation of Table 3 and containing paucilamellar vesicles wasprepared as in Example 1 above. After the single addition componentswere added, a slurry of water and Cabopol ETD 2020 was added to thecomposition. Mirasil DM 100 and Phenoxetol were added theretosequentially under mixing at 200 rpm for about 30 minutes. Theformulation was allowed to cool to about 25 E C under ambientconditions. The composition did not contain ammonium hydroxide.

TABLE 3 TRADE NAME CHEMICAL NAME FUNCTION % WT/WT LIPID PHASE Brij 76Steareth-10 Emulsifier 1.4 Kessco GDS Glyceryl Distearate Emulsifier 2.8Cholesterol NF Cholesterol Emulsifier 1 Procol ST 20G Ceteareth-20 &Stearyl Emulsifier 3 Alcohol Procol CS 20D Cereareth-20 & CetearylEmulsifier 3 Alcohol Lanol S Stearyl Alcohol Skin 0.5 ConditionerWickenol 171 Octyl Hydroxystearate Conditioning 5.8014 Agent BHT BHTAntioxidant 0.1 Tween 80 Polysorbate 80 Emulsifier 0.7 Retinol 50CJ**Retinol in Polysorbate-20 Skin 0.25 Conditioner AQUEOUS PHASE Eaupurifiee Aqua Vehicle 41.0843 Pricerin 9099 Glycerin Humectant 4Methylparaben Methylparaben Preservative 0.25 PropylparabenPropylparaben Preservative 0.15 Disodium EDTA Disodium EDTA Chelator 0.1Lactose Lactose Humectant 5 Rectapur Glypure 70% Glycolic acid (70%)Skin 5.7143 Conditioner Sodium Sodium Hydroxide pH Adjuster 1.32Hydroxide Eau purifiee Aqua Vehicle 20 Carbopol ETD Acrylates/C10-30Alkyl Thickener 0.6 2020 Acrylate crosspolymer SINGLE ADDITIONCOMPONENTS Mirasil DM 100 Dimethicone Skin 2.5 Conditioner PhenoxetolPhenoxyethanol Preservative 0.73 **Retinol 50CJ is available from BASFof Mount Olive, NJ, and contains 50% by weight of retinol.

A control having the formulation of Table 3 was prepared excludingammonium hydroxide and sodium hydroxide (Example 5A). The compositionand control were applied to skin, and the pH of the skin was measuredover time. Results are illustrated in FIG. 4.

EXAMPLE 6

A retinol/alpha-hydroxy acid containing composition having theformulation of Table 4 and a pH of about 5.8 was prepared as describedin Example 5, except 3% by weight of ammonium hydroxide was substitutedfor the sodium hydroxide in Example 5.

TABLE 4 TRADE NAME CHEMICAL NAME FUNCTION % WT/WT Brij 76 Steareth-10Emulsifier 1.4 LIPID PHASE Kessco GDS Glyceryl Distearate Emulsifier 2.8Cholesterol NF Cholesterol Emulsifier 1 Procol ST 20G Ceteareth-20 &Stearyl Emulsifier 3 Alcohol Procol CS 20D Cereareth-20 & Emulsifier 3Cetearyl Alcohol Lanol S Stearyl Alcohol Emulsifier 0.5 Wickenol 171Octyl Hydroxystearate Emulsifier 5.8014 BHT BHT Antioxidant 0.1 Tween 80Polysorbate 80 Emulsifier 0.7 Retinol 50CJ** Retinol in Skin 0.25Polysorbate-20 Conditioner Eau purifiee Aqua Vehicle 39.4043 AQUEOUSPHASE Pricerin 9099 Glycerin Humectant 4 Methylparaben MethylparabenPreservative 0.25 Propylparaben Propylparaben Preservative 0.15 DisodiumEDTA Disodium EDTA Chelator 0.1 Lactose Lactose Humectant 5 RectapurGlypure 70% Glycolic acid (70%) Skin 5.7143 Conditioner AmmoniumAmmonium Hydroxide pH Adjuster 3 Hydroxide (30%) Eau purifiee AquaVehicle 20 Carbopol ETD Acrylates/C10-30 Thickener 0.6 2020 AlkylAcrylate crosspolymer SINGLE ADDITION COMPONENTS Mirasil DM 100Dimethicone Skin 2.5 Conditioner Phenoxetol Phenoxyethanol Preservative0.73 **Retinol 50CJ is available from BASF of Mount Olive, NJ, andcontains 50% by weight of retinol.

A control having the formulation of Table 4 was prepared excludingammonium hydroxide (Example 6A). The composition and control wereapplied to skin, and the pH of the skin was measured over time. Resultsare illustrated in FIG. 4.

EXAMPLES 7 AND 8

Two retinol/alpha-hydroxy acid containing liposomal compositions havingthe formulations of Table 5 below are prepared as follows.

TABLE 5 CHEMICAL Example 7 Example 8 TRADE NAME NAME Function (% W/W) (%W/W) Ranges LIPID PHASE Glyceryl Glyceryl Nonionic 2.8 2.8 1.4-8.4Dilaurate Dilaurate Surfactant Cholesterol Cholesterol Nonionic 0.9 0.90.45-2.7  Surfactant POE 10 Stearyl POE 10 Stearyl Nonionic 2.5 2.51.25-7.5  Alcohol Alcohol Surfactant Laureth-9 Laureth-9 Nonionic 1.241.24 0.62-3.72 Surfactant Butylated BHT Anti-oxidant 0.05 0.05 0-3Hydroxytoluene (BHT) Retinol 50C ™ Retinol in Skin 0.2 0.4 0.01-2  Polysorbate-20 Conditioner AQUEOUS PHASE Citric Acid Citric AcidAnti-oxidant 0.4 0.4 0.1-0.8 Trisodium Trisodium Buffer 0.6 0.6 0.1-0.8Citrate Citrate dihydrate dihydrate Ascorbic Acid Ascorbic AcidAnti-oxidant 0.01 0.01 0.01-0.1  Glycerin Glycerin Humectant 0 4.0  0-20Disodium EDTA Disodium EDTA Chelating 0.2 0.2 0.01-0.2  AgentPreservative Phenoxyethanol Phenoxyethanol Preservative 0.5 0.50.01-0.5  Methylparaben Methylparaben Preservative 0.25 0.25 0.01-0.2 Propylparaben Propylparaben Preservative 0.15 0.15 0.01-0.2  Glypure(70%) Skin 5.71 5.71 0.01-15   Conditioner Ammonium Ammonium pH adjuster3.2 3.2 0.01-10   Hydroxide Hydroxide (pH = 6) (27 to 31%) (27 to 31%)Water Water Carrier 81.29 77.06 40-90These compositions may be prepared by the following two methods.1. Shear Mixing Method: Appropriate amounts of the lipid phaseingredients are mixed in a container heated to about 75° C. until allthe lipids have melted. The lipid melt is then cooled to about 65° C.The aqueous phase ingredients are mixed and heated to about 75° C. todissolve them and then cooled to about 60° C. The lipid melt and aqueousphase mixture are poured into separate holding reservoirs of a shearmixing apparatus for preparing liposomes as described in U.S. Pat. No.4,895,452. The positive displacement pump for the lipid and aqueous feedlines is turned on. The feed rate will depend on the desired viscosityof the composition. For a thinner consistency, a feed rate of 1 partlipid to 9 parts aqueous phase may be utilized. For thickerconsistencies, a feed rate of 1 part lipid phase to 4 parts aqueousphase may be utilized. After the feed rate is adjusted, valves to thefeed lines are opened and the aqueous phase mixture and lipid melt arefed through injection jets into a cylindrical mixing chambertangentially with respect to the cylinder wall. In the mixing chamber,the two streams of liquid intersect in such a manner as to cause shearmixing that causes the formation of liposomes. The liposomes are thenwithdrawn through an exit tube.2. Syringe Method: Appropriate amounts of the lipid phase ingredientsare mixed in a beaker at 75° C. until the lipids melt. The lipid melt isdrawn into a syringe, which was preheated in a water bath to about 75°C. A second syringe containing appropriate amounts of the aqueous phaseingredients is preheated in a water bath to about 70° C. The twosyringes were then connected via a 3-way metal stopcock. The ratio ofaqueous phase mixture to lipid phase mixture was about 4:1 or 4 ml ofaqueous phase mixture to 1 ml of lipid phase mixture. The ratio ofaqueous phase mixture to lipid phase mixture can be adjusted to obtainthe desired viscosity. After injecting the aqueous phase mixture intothe lipid phase mixture, the resulting mixture is rapidly mixed back andforth between the two syringes several times until the contents cool toabout 25-30° C.

EXAMPLES 9 AND 10

Two oil-in-water emulsions of the present invention are shown in Table6.

TABLE 6 CHEMICAL Example 9 Example TRADE NAME NAME Function (% W/W) 10(% W/W) Ranges OIL PHASE Cetearyl Cetearyl Surfactant 1.4 1.4 0.1-2.8Glucoside Glucoside C12-15 Alkyl C12-15 Alkyl Surfactant 4.0 4.0 1-6Benzoate Benzoate Octyl Octyl Emollient 1.0 1.0 0-5 HydroxystearateHydroxystearate Dimethicone Dimethicone Spreading 1.0 1.0 0-5 AgentCyclomethicone Cyclomethicone Spreading 1.0 1.0 0-5 Agent Cetyl AlcoholCetyl Alcohol Emollient 2.5 2.5 0-4 Butylated BHT Anti-oxidant 0.05 0.050-3 Hydroxytoluene Octyl Octyl Sunscreen 6.0 6.0  0-10 MethoxycinnamateMethoxycinnamate Propylparaben Propylparaben Preservative 0.5 0.1  0-0.5 Vitamin E Vitamin E Anti-oxidant 0.5 0.5   0-0.5 acetate acetateRetinol Retinol Anti-Wrinkle 0.25 0.4 0.01-5   Tocopherol TocopherolAnti-oxidant 0.5 0.5   0-0.5 Acetate Acetate AQUEOUS PHASE GlycerinGlycerin Humectant 3.0 3.0  0-20 D-Pathenol D-Pathenol Pro-Vitamin 0.50.5 0-5 Disodium EDTA Disodium EDTA Chelator, 0.1 0.1 0.01-1   whiteningagent Methyl Paraben Methyl Paraben Preservative 0.2 0.2   0-0.3Carbomer Thickener 0.35 0.35 0-3 Glycolic acid Glycolic acid Skin 5.715.71  0-15 (70%) (70%) Conditioner Ammonium Ammonium pH adjuster 3.2 3.20-1 Hydroxide Hydroxide Deionized Water Deionized Water Carrier 68.1968.04 50-80

Each emulsion is prepared by mixing the oil phase ingredients andheating the mixture to about 85° C. The oil phase mixture is then cooledto about 60° C.

In a separate vessel, the carbomer is slowly added to the water. Aftermixing for about 10 minutes the remaining aqueous phase ingredients areadded and the mix is heated to about 60° C.

The two phases are then combined, mixed for about 10 minutes, and cooledto room temperature. One or more depigmentation agents may be added tothe formulations in these examples.

EXAMPLES 11 AND 12

Two water-in-oil emulsions of the present invention are shown in Table7.

TABLE 7 CHEMICAL Example 11 Example 12 Preferred TRADE NAME NAMEFunction (% W/W) (% W/W) Ranges OIL PHASE Mineral Oil Mineral OilEmollient 25.0 25.0 40-80 Sorbitan Sorbitan Surfactant 5.0 5.0 1-6Monooleate Monooleate Stearyl Alcohol Stearyl Emollient 25.0 25.0 20-60Alcohol Dimethicone Dimethicone Spreading 1.0 1.0 1-5 Agent CetylAlcohol Cetyl Emollient 2.0 2.0 0.1-10  Alcohol HydrogenatedHydrogenated Anti-oxidant 3.0 3.0  0-10 Lecithin Lecithin Parsol MCXSunscreen 3.0 3.0  0-10 Butylated BHT Anti-oxidant 0.05 0.05 0-3Hydroxytoluene Retinol Retinol Anti-Wrinkle 0.25 0.4 0.01-5  Propylparaben Propylparaben Preservative 0.5 0.5 0.01-0.5  Vitamin EVitamin E Anti-oxidant 0.5 0.5 0.01-0.5  acetate acetate AQUEOUS PHASEGlycerin Glycerin Humectant 3.0 3.0  0-20 Methyl Paraben MethylPreservative 0.2 0.2 0.01-0.3  Paraben Water Water Carrier 22.59 22.4420-45 Glycolic acid Glycolic Skin 5.71 5.71  0-15 (70%) acid (70%)Conditioner Ammonium Ammonium pH adjuster 3.2 3.2 0-1 HydroxideHydroxide

Each emulsion is prepared by melting stearyl alcohol and mineral oil atabout 70° C. The other oil phase ingredients are added and the mixtureis heated to about 75° C. The aqueous phase ingredients are dissolved inwater and warmed to about 70° C. The aqueous phase mixture is added tothe oil phase mixture. The resulting mixture is stirred until itcongeals.

EXAMPLE 13

An oil-in-water emulsion of the present invention is shown in Table 8.

The emulsion is prepared by mixing the oil phase ingredients and heatingthe mixture to about 85° C. The oil phase mixture is then cooled toabout 60° C. In a separate vessel, the water phase ingredients areadded, mixed and heated to about 60° C.

The two phases are then combined, mixed for about 10 minutes, and cooledto about 35° C., at which time the post additions are added and mixed,followed by the addition and mixing of the glycolic acid/malicacid/deionized water buffer pre-mix. The retinol 50C is then added andmixed last.

TABLE 8 CTFA Name Trade Name FUNCTION Wt. % OIL PHASE C12-15 AlkylFinsolv TN Solubilizing Agent 4.00 Benzoate Octyl Wickenol 171 emolient1.00 Hydroxystearate Dimethicone, 100 Dimethicone 47V-100 emolient 1.00centistoke Steareth 2 Brij 72 emulsifier 0.60 Cetyl Alcohol Cetalemolient, 2.50 emulsifier Steareth 20 Brij 721 emulsifier 0.90 BHT BHTantioxidant for 0.10 cosmetics Pemulen TR1 Acrylates/C10-30 thickener/0.50 Alkyl emulsifier Acrylate Crosspolymer WATER PHASE Deionized WaterWater Solvent 62.59 Disodium EDTA EDTA Chelating Agent 0.10 GlycerinGlycerin 916 99.7% humectant, 3.00 USP emollient Panthenol D-PanthenolU.S.P. moisturizing agent 0.50 FCC Phenoxyethanol Emeressence 1160perservative 0.73 Methylparaben Methylparaben preservative 0.35Propylparaben Propylparaben preservative 0.17 POST ADDITIONSDMAE/Tyrosine L-Tyrosine active 0.50 Pre-mix L-Tyrosine Deionized WaterDeionized Water solvent 15.00 DMAE 2-(dimethylamino)- active 3.00ethanol BUFFER PRE-MIX Glycolic Acid Glypure 70 buffer 1.20 Malic AcidMalic Acid buffer 0.84 Deionized Water Deionized Water Solvent 1.32Retinol 50C Vitamin A alcohol in vitamin A 0.10 Polysorbate 80

All patents, publications, applications, and test methods mentionedherein are hereby incorporated by reference.

Many variations of the present invention will suggest themselves tothose skilled in the art in light of the above, detailed description.All such obvious variations are within the full intended scope of theappended claims.

1. A composition comprising: (A) retinol; (B) a dermatologically activeacid selected from the group consisting of lactic acid, glycolic acid,malic acid, tartaric acid, pyruvic acid, citric acid, salicylic acid,and ascorbic acid; and (C) 2-dimethylaminoethanol; wherein saidcomposition has a pH of from about 5 to about 6 and wherein said retinoland said acid are stable and active upon application to the skin.
 2. Acomposition as defined in claim 1, wherein said dermatologically activeacid is ascorbic acid.
 3. A composition as defined in claim 1, whereinsaid dermatologically active acid is glycolic acid.
 4. A composition asdefined in claim 1, wherein said dermatologically active acid issalicylic acid.
 5. A composition as defined in claim 1, wherein saidretinol comprises from about 0.01 to about 10 percent by weight, basedupon 100 percent by weight of total composition.
 6. A composition asdefined in claim 5, wherein the amount of said dermatologically activeacid ranges from about 0.1 to about 20 percent by weight, based upon 100percent by weight of total composition.
 7. A composition as defined inclaim 3, said composition comprises from about 0.01 to about 10 percentby weight of retinol and from about 0.1 to about 20 percent by weight ofsaid glycolic acid, based upon 100 percent of total composition.
 8. Acomposition as defined in claim 4, said composition comprises from about0.01 to about 10 percent by weight of retinol and from about 0.1 toabout 20 percent by weight of said salicylic acid, based upon 100percent of total composition.
 9. A composition as defined in claim 1,further comprising a second neutralizing agent.
 10. A composition asdefined in claim 9, wherein said second neutralizing agent comprises analkali hydroxide, alkanolamine, amino acid, or any combination of any ofthe foregoing.
 11. A composition as defined in claim 10, wherein saidsecond neutralizing agent comprises sodium hydroxide, potassiumhydroxide, diethanolamine, triethanolamine, aminobutanol, arginine,lysine, or any combination of any of the foregoing.
 12. A compositioncomprising: (A) retinol; and (B) a salt formed by 2-dimethylaminoethanoland a dermatologically active acid selected from the group consisting oflactic acid, glycolic acid, malic acid, tartaric acid, pyruvic acid,citric acid, salicylic acid, and ascorbic acid; wherein said compositionhas a pH of from about 5 to about 6 and wherein said retinol and saidacid are stable and active upon application to the skin.
 13. Acomposition as defined in claim 12, wherein said dermatologically activeacid is ascorbic acid.
 14. A composition as defined in claim 12, whereinsaid dermatologically active acid is glycolic acid.
 15. A composition asdefined in claim 12, wherein said dermatologically active acid issalicylic acid.
 16. A composition as defined in claim 12, wherein saidretinol comprises from about 0.01 to about 10 percent by weight, basedupon 100 percent by weight of total composition.
 17. A composition asdefined in claim 16, wherein the amount of said salt ranges from about0.1 to about 20 percent by weight, based upon 100 percent by weight oftotal composition.
 18. A composition as defined in claim 14, saidcomposition comprises from about 0.01 to about 10 percent by weight ofretinol and from about 0.1 to about 20 percent by weight of said salt,based upon 100 percent of total composition.
 19. A composition asdefined in claim 15, said composition comprises from about 0.01 to about10 percent by weight of retinol and from about 0.1 to about 20 percentby weight of said salt, based upon 100 percent of total composition. 20.A composition as defined in claim 12, further comprising (C) at leastone second neutralized salt, other than N,N-dimethylethanolammoniumsalt, of a dermatologically active acid.
 21. A composition as defined inclaim 20, wherein said second neutralized salt is a salt of an alkalihydroxide, alkanolamine, amino acid, or any combination of any of theforegoing.
 22. A composition as defined in claim 20, wherein said secondneutralized salt is a salt of sodium hydroxide, potassium hydroxide,diethanolamine, triethanolamine, aminobutanol, arginine, lysine, or anycombination of any of the foregoing.